Peroxisome proliferator-activated receptor γ (PPARγ) ligands improve human hypertension. However, the mechanism and site of this effect remains unknown, confounded by PPARγ expression in many cell types, including endothelial cells (ECs).

To evaluate the vascular role of PPARγ we used a conditional null mouse model. Specific disruption of PPARγ in ECs was created by crossing Tie2-Cre+ transgenic (T2T+) and PPARγ-floxed (fl/fl) mice to generate PPARγ (fl/fl)T2T+ (PPARγ E-null) mice. Conscious 8- to 12-week-old congenic PPARγ (fl/fl)Cre− (wild type) and PPARγ E-null mice were examined for changes in systolic blood pressure (BP) and heart rate (HR), untreated, after 2 months of salt-loading (drinking water), and after treatment for 3 months with high fat (HF) diet alone or supplemented during the last 2 weeks with rosiglitazone (3 mg/kg/d).

Untreated PPARγ E-nulls were phenotypically indistinguishable from wild-type littermates. However, compared to similarly treated wild types, HF-treated PPARγ -nulls had significantly elevated systolic BP not seen after normal diet or salt-loading. Despite sex-dependent baseline differences, salt-loaded and HF-treated PPARγ -nulls of either sex had significantly elevated HR versus wild types. Interestingly, rosiglitazone improved serum insulin levels, but not HF diet-induced hypertension, in PPARγ -null mice.

These results suggest that PPARγ in ECs not only is an important regulator of hypertension and HR under stressed conditions mimicking those arising in type 2 diabetics, but also mediates the antihypertensive effects of rosiglitazone. These data add evidence supporting a beneficial role for PPARγ-specific ligands in the treatment of hypertension, and suggest therapeutic strategies targeting ECs may prove useful. Am J Hypertens 2005;18:549–556 © 2005 American Journal of Hypertension, Ltd.